Most pharmaceutical suspension aerosol formulations currently use a mixture of liquid chlorofluorocarbons as the propellant. Fluorotrichloromethane, dichlorodifluoromethane and dichlorotetrafluoroethane arc the most commonly used propellants in aerosol formulations for administration by inhalation.
Chlorofluorocarbons (CFCs), however, have been implicated in the destruction of the ozone layer and their production is being phased out. Hydrofluorocarbon 134a (HFA 134a, 1,1,1,2-tetrafluoroethane) and hydrofluorocarbon 227 (HFA 227, 1,1,1,2,3,3,3-heptafluoropropane) are viewed as being more ozone friendly than many chlorofluorocarbon propellants; furthermore, they have low toxicity and vapor pressures suitable for use in aerosols.
W091/11495 and W091/11496 disclose pharmaceutical suspension aerosol formulations comprising a medicinal agent, a surfactant, and a propellant mixture containing 1,1,1,2,3,3,3-heptafluoropropane and one or more additional components, e.g. pentane, butane, propellant 134a , propellant 11, propellant 125, or propellant 152a.
EP 0384371 discloses solution aerosols in which 1,1,1,2,3,3,3-heptafluoropropane or its mixture with propane, butane, isobutane, dimethyl ether, or 1,1, difluoroethane serves as the propellant. The application does not, however, disclose suspension aerosols or pharmaceutical aerosol formulations.
EP 0372777 discloses, inter alia, examples of aerosol formulations comprising a medicament, 1,1,1,2-tetrafluoroethane, a surface active agent, and at least one compound having higher polarity than 1,1,1,2-tetrafluoroethane.
U.S. Pat. No. 2,868,691 discloses aerosol formulations comprising a medicament, a halogenated lower alkane propellant, and a co-solvent which assists in dissolving the medicament in the propellant. The chemical formula for the propellant given in column 2, lines 6 to 16, generically embraces HFA 134a and HFA 227. Examples of co-solvents disclosed include ethanol and diethyl ether.
U.S. Pat. No. 3,014,844 discloses aerosol formulations comprising a micronised medicament, a halogenated lower alkane propellant and a surface-active agent to assist in the suspension of the medicament in the propellant. The chemical formula for the propellant given in column 4, lines 17 to 28, generically embraces HFA 134a and HFA 227.
W091/04011 discloses aerosol compositions having HFA 134a as the propellant and comprising a medicament coated with a non-perfluorinated surface active dispersing agent.
W093/11747 discloses a pharmaceutical suspension formulation suitable for aerosol administration, consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. The application specifically discloses formulations of Formoterol Fumarate in HFA 134a, HFA 227 and 1:1 mixtures of HFA 134a and HFA 227. The formulations do not contain surfactants or ethanol. It is stated that mixtures of HFA 134a and HFA 227 may be adjusted for density matching with the drug.
W093/11745 discloses pharmaceutical aerosol formulations, substantially free of surfactant containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants and up to 5% of a polar co-solvent. Preferred propellants are HFA 134a and HFA 227 which are preferably used alone. The preferred polar co-solvent is ethanol and it is stated that in general only small quantities e.g. 0.05 to 3.0% w/w of polar co-solvent are required to improve the dispersion and the use of quantities in excess of 5% w/w may disadvantageously tend to dissolve the medicament.
EP-A-0504112 discloses a pharmaceutical composition for aerosol use containing:
(a) a liquefied propellant gas or propellant gas mixture with a vapor pressure exceeding 1 bar but less than 6 bar (20.degree. C.) from the unsubstituted or partially to completely fluorinated hydrocarbon group; PA1 (b) a non-ionic tensile of the monoacetylated or diacetylated monoglyceride group; PA1 (c) a pharmaceutical active substance or combination of active substances, and, if necessary, PA1 (d) other common pharmaceutical accessory substances suitable for aerosol formulations. PA1 (a) from 0.0025 to 0.1% w/w of micronized Formoterol, or an acid addition salt thereof and PA1 (b) from 0.1 to 5.0% w/w ethanol, PA1 (c) HFA 134a, HFA 227 or a mixture of HFA 227 and HFA 134a and optionally PA1 (d) a surfactant other than a monoacetylated or diacetylated monoglyceride, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug. PA1 (a) from 0.0025 to 0.1% w/w of micronised Formoterol, or an acid addition salt thereof, PA1 (b) from 0.1 to 5.0% w/w ethanol, PA1 (c) a propellant consisting of HFA 134a, HFA 227 or a mixture of HFA 227 and HFA 134a, PA1 (d) a micronised bulking agent in a weight ratio in the range from 1:3 to 1:100 of Formoterol: bulking agent, and optionally PA1 (e) a surfactant, the formulation being further characterized in that it exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, is substantially and readily redispersible, and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug.
It is stated the basic purpose of that invention was to find a special accessory suspending substance for active substances in aerosol formulations, which dissolves better in liquefied "alternative" propellant gases than the accessory suspending substances hitherto recognized and used. Surprisingly, it was discovered, in solving this problem, that non-ionic tensides of the monoacetylated or diacetylated monoglyceride group are very soluble in the "alternative" propellant gases mentioned, particularly in heptafluoropropane (HFA 227), are beneficial to the production of homogenous suspensions, and also have outstanding metering valve lubrication properties. Some of the examples of EP-A-0504112 disclose formulations comprising Formoterol Fumarate.
Formoterol Fumarate is a long acting B.sub.2 agonist which has been developed for delivery to the respiratory system by a metered dose inhaler (MDI). The drug is highly potent and its dosage is considerably less than many other drugs which have been administered by MDIs. Thus, the concentration of Formoterol Fumarate in aerosol formulations is very low and this factor, together with other properties of the drug have led to problems in manufacturing and formulating a composition which is stable and provides good dosage reproducibility when administered by MDIS.
Aerosol formulations consisting of propellant, e.g. HFA 134a, HFA 227 and mixtures thereof, and Formoterol Fumarate without additional excipient sometimes encounter problems such as caking on manufacturing equipment, high deposition in the vial or valve of inhalers and valve sticking.
Aerosol compositions consisting of Formoterol Fumarate, HFA 134a and ethanol have proved to be extremely sensitive to ethanol concentration. An ethanol concentration of 3.5% w/w may cause unacceptable crystal growth.